Production process of optically active 3-quinuclidinol derivative

ABSTRACT

A process is provided for efficiently producing an optically active 3-quinuclidinol derivative of high optical purity using a readily available ruthenium compound as an asymmetric reduction catalyst. This process is a process for producing an optically active 3-quinuclidinol derivative represented by the following formula (III) comprising asymmetrically hydrogenating a 3-quinuclidinone derivative represented by the following formula (I) in the presence of a ruthenium compound (II) represented by formula (II): Ru(X)(Y)(Px) n [R 1 R 2 C*(NR 3 R 4 )-A-R 5 R 6 C*(NR 7 R 8 )] (in the formulas, R represents a hydrogen atom or C7 to C18 aralkyl group and the like, X and Y represent hydrogen atoms or halogen atoms and the like, Px represents a phosphine ligand, n represents 1 or 2, R1 to R8 represent hydrogen atoms or C1 to C20 alkyl groups and the like, * represents an optically active carbon atom and A represents an ethylene group and the like).

This application is a national phase application of PCT/JP2008/065746filed on Sep. 2, 2008 which claims priority under 35 U.S.C. 119 toJapanese Patent Application Nos. 2007-230973 filed Sep. 6, 2007 and2008-032311 filed Feb. 13, 2008.

TECHNICAL FIELD

The present invention relates to a process for producing opticallyactive 3-quinuclidinol derivatives that are useful as production rawmaterials of physiologically active substances, and particularlypharmaceuticals.

The present application claims priority on Japanese Patent ApplicationNo. 2007-230973, filed on Sep. 6, 2007, and Japanese Patent ApplicationNo. 2008-032311, filed on Feb. 13, 2008, the contents of which areincorporated herein by reference.

BACKGROUND OF THE ART

Many alkaloids, and particularly those compounds having an azabicycloring structure, are useful as physiologically active substances. Inparticular, optically active 3-quinuclidinol derivatives are importantcompounds as production raw materials of pharmaceuticals.

A conventionally known process for industrial production of opticallyactive 3-quinuclidinol consists of direct asymmetric hydrogenation of3-quinuclidinone using inexpensive hydrogen gas for the hydrogen sourcein the presence of an asymmetric hydrogenation catalyst (PatentDocuments 1 to 4).

In this production process, an optically active transition metal complexhaving an optically active diphosphine and 1,2-diamine as ligands isused for the asymmetric hydrogenation catalyst.

For example, the optically active transition metal complex described inPatent Document 1 has a bisbinaphthyl compound derivative having anasymmetric axis for the optically active diphosphine ligand, thatdescribed in Patent Document 2 has a bisbiphenyl compound derivativehaving an asymmetric axis for the optically active diphosphine ligand,that described in Patent Document 3 has a ferrocene compound derivativehaving an optically active group in a side chain thereof for theoptically active diphosphine ligand, and that described in PatentDocument 4 has an alkane compound derivative having an asymmetric carbonfor the optically active diphosphine ligand. In addition, the opticallyactive transition metal complexes of all of these patent, documents haveoptically active or racemic 1,2-diamine compounds as diamine ligands.Hydrogenation reactions are allowed to proceed under mild conditions byall of the asymmetric hydrogenation catalysts described in thesepublications.

However, the processes described in Patent Documents 1 and 3 have lowenantiomeric excess for the resulting quinuclidinol and low catalystefficiency, the process described in Patent Document 2 has low catalystefficiency, and the process described in Patent Document 4 has lowenantiomeric excess for the resulting quinuclidinol.

Thus, there is a desire for the development of a process that enablesdirect asymmetric hydrogenation of 3-quinuclidinone having highattainment rates for both enantiomeric excess and catalyst efficiency.

-   -   [Patent Document 1] Japanese Unexamined Patent Application,        First Publication No. 2003-277380    -   [Patent Document 2] Japanese Unexamined Patent Application,        First Publication No. 2005-306804    -   [Patent Document 3] Japanese Unexamined Patent Application,        First Publication No. 2004-292434    -   [Patent Document 4] International Publication No. WO 2006-103756

DISCLOSURE OF THE INVENTION

[Problems to be Solved by the Invention]

With the foregoing in view, an object of the present invention is toprovide a process for efficiently producing 3-quinuclidinol derivativesof high optical purity by direct asymmetric hydrogenation of3-quinuclidinone derivatives at high attainment rates for bothenantiomeric excess (or enantiomeric excess and diastereomeric excess)and catalyst efficiency.

[Means for Solving the Problems]

In order to solve the aforementioned problems, the inventors of thepresent invention conducted extensive studies on processes for directasymmetric hydrogenation of 3-quinuclidinone derivatives usinginexpensive hydrogen gas for the hydrogen source in the presence of anasymmetric hydrogenation catalyst. As a result, the inventors of thepresent invention found that the use of a readily available opticallyactive ruthenium metal complex having a diphosphine ligand and a1,4-dimaine ligand for the asymmetric hydrogenation catalyst enabled3-quinuclidinol derivatives of high optical purity to be produced athigh yield by direct asymmetric hydrogenation of 3-quinuclidinonederivatives at high attainment rates for both enantiomeric excess (orenantiomeric excess and diastereomeric excess) and catalyst efficiency,thereby leading to completion of the present invention.

Thus, according to the present invention, a process for producingoptically an active 3-quinuclidinol derivative is provided as indicatedin (1) to (5) below.

-   (1) A process is provided for producing an optically active    3-quinuclidinol derivative represented by formula (III):

(wherein, R represents a hydrogen atom, an unsubstituted or substitutedC1 to C20 alkyl group, an unsubstituted or substituted C2 to C20 alkenylgroup, an unsubstituted or substituted C3 to C8 cycloalkyl group, anunsubstituted or substituted C5 to C6 cycloalkenyl group, anunsubstituted or substituted C7 to C18 aralkyl group or an unsubstitutedor substituted C6 to C18 aryl group, and * represents an opticallyactive carbon atom), comprising: asymmetrically hydrogenating a3-quinuclidinone derivative represented by formula (I):

(wherein,

R is the same as previously defined) in the presence of a rutheniumcompound represented by formula (II):Ru(X)(Y)(Px)_(n)[R¹R²C*(NR³R⁴)-A-R⁵R⁶C*(NR⁷R⁸)]  (II)(wherein,

X and Y respectively and independently represent a hydrogen atom, ahalogen atom, a carboxylate, a hydroxyl group or a C1 to C20 alkoxygroup;

Px represents a phosphine ligand;

n represents 1 or 2;

R¹ to R⁸ respectively and independently represent a hydrogen atom, anunsubstituted or substituted C1 to C20 alkyl group, an unsubstituted orsubstituted C2 to C20 alkenyl group, an unsubstituted or substituted C3to C8 cycloalkyl group, an unsubstituted or substituted C5 to 06cycloalkenyl group, an unsubstituted or substituted C7 to 018 aralkylgroup or an unsubstituted or substituted C6 to C18 aryl group, or eitherof R¹ and R² may bond with either of R³ and R⁴, and either of R⁵ and R⁶may bond with either of R⁷ and R⁸, to form a ring;

* is the same as previously defined; and,

A represents an unsubstituted or substituted C1 to C3 alkylene groupthat may have ether bond(s), an unsubstituted or substituted C3 to C8cycloalkylene group, an unsubstituted or substituted arylene group or anunsubstituted or substituted divalent heterocyclic group, and in thecase A is an unsubstituted or substituted C1 to C3 alkylene group,either of R¹ and R² and either of R⁵ and R⁶ may bond to form a ring).

-   (2) A process for producing an optically active 3-quinuclidinol    derivative represented by formula (III-1):

(wherein,

R and * are the same as previously defined, and ** represents anoptically active carbon atom in the case R is other than a hydrogenatom), comprising: asymmetrically dehydrogenating a 3-quinuclidinonederivative represented by formula (I-1):

(wherein, R is the same as previously defined) in the presence of aruthenium compound represented by the formula (II).

-   (3) The process for producing an optically active 3-quinuclidinol    derivative described in (1) or (2) above, wherein the ruthenium    compound represented by formula (II) is a ruthenium compound    represented by formula (II-1):    Ru(X)(Y)(Px)_(n)[R¹C*H(NR³R⁴)-A-R¹C*H(NR³R⁴)]  (II-1)    (wherein, X, Y, Px, n, R¹, R³, R⁴, * and A are the same as    previously defined).-   (4) The process for producing an optically active 3-quinuclidinol    derivative described in (1) or (2) above, wherein the ruthenium    compound represented by formula (II) is a ruthenium compound    represented by formula (II-2):    Ru(X)(Y)(Px)_(n)[R¹C*H(NH₂)-A-R¹C*H(NH₂)]  (II-2)    (wherein, X, Y, Px, n, and * and A are the same as previously    defined).-   (5) The process for producing an optically active 3-quinuclidinol    derivative described in (1) or (2) above, wherein the ruthenium    compound represented by formula (II) is a ruthenium compound    represented by formula (II-3):    Ru(X)₂(Pxx)[R¹C*H(NH₂)-A-R¹C*H(NH₂)]  (II-3)    (wherein, X, R¹, * and A are the same as previously defined, and Pxx    represents an optically active phosphine ligand).    Effects of the Invention

According to the present invention, an optically active 3-quinuclidinolderivative of high optical purity can be produced at high attainmentrates for enantiomeric excess or diastereomeric excess and catalystefficiency by using a readily available ruthenium compound as anasymmetric reduction catalyst.

BEST MODE FOR CARRYING OUT THE INVENTION

The following provides a detailed explanation of the present invention.

The present invention is a process for producing an optically active3-quinuclidinol derivative represented by the formula (III) thatcomprises asymmetric dehydrogenation of a 3-quinuclidinone derivativerepresented by the formula (I) in the presence of a ruthenium compoundrepresented by the formula (II).

3-Quinuclidinone Derivative (I)

In the present invention, the 3-quinuclidinone derivative represented bythe formula (I) (to be referred to as the “3-quinuclidinone derivative(I)”) is used as a starting raw material.

In the formula (I), R represents a hydrogen atom, an unsubstituted orsubstituted C1 to C20 alkyl group, an unsubstituted or substituted C2 toC20 alkenyl group, an unsubstituted or substituted C3 to C8 cycloalkylgroup, an unsubstituted or substituted C5 to C6 cycloalkenyl group, anunsubstituted or substituted C7 to C18 aralkyl group or an unsubstitutedor substituted C6 to C18 aryl group.

Examples of C1 to C20 alkyl groups include a methyl group, ethyl group,n-propyl group, i-propyl group, n-butyl group, s-butyl group, t-butylgroup, n-pentyl group and n-hexyl group.

Examples of C2 to C20 alkenyl groups include a vinyl group, 1-propenylgroup, 2-propenyl group, 1-n-butenyl group, 1-s-butenyl group,1,3-butadienyl group, 1-n-pentenyl group, 2-n-pentenyl group,3-n-pentenyl group and 2-n-hexenyl group.

Examples of C3 to C8 cycloalkyl groups include a cyclopropyl group,cyclobutyl group, cyclopentyl group and cyclohexyl group.

Examples of C5 to C6 cycloalkenyl groups include a 1-cyclopentenylgroup, 2-cyclopentenyl group, 1-cyclohexenyl group, 2-cyclohexenyl groupand 3-cyclohexenyl group.

Examples of C7 to C18 aralkyl groups include a benzyl group,α,α-dimethylbenzyl group, phenethyl group and benzhydryl group.

Examples of C6 to C18 aryl groups include a phenyl group, 1-naphthylgroup, 2-naphthyl group and 3-anthracenyl group.

There are no particular limitations on the type or number ofsubstituents of the C1 to C20 alkyl groups and C2 to C20 alkenyl groupsprovided they are within a chemically acceptable range. Examples ofthese substituents include halogen atoms such as a fluorine atom,chlorine atom, bromine atom or iodine atom; hydroxyl groups; C1 to 020alkoxy groups such as a methoxy group, ethoxy group, n-propoxy group,i-propoxy group, n-butoxy group, s-butoxy group, i-butoxy group ort-butoxy group; C7 to C18 aralkyloxy groups such as a benzyloxy group,α,α-dimethylbenzyloxy group or phenethyloxy group; acylamino groups suchas an acetylamino group or benzoylamino group; sulfonylamino groups suchas a methanesulfonylamino group or toluenesulfonylamino group;N-alkyl-N-acylamino groups such as an N-methyl-N-acetylamino group,N-ethyl-N-acetylamino group, N-methyl-N-benzoylamino group orN-ethyl-N-acylamino group; N-alkyl-N-alkylsulfonylamino groups such asN-methyl-N-methylsulfonylamino group or N-ethyl-N-methylsulfonylaminogroup; phthalimido groups; and oxygen-containing heterocyclic groupssuch as a furanyl group, pyranyl group or dioxolanyl group.

There are no particular limitations on the type or number ofsubstituents of the C7 to C18 aralkyl groups, C6 to C18 aryl groups, C3to C8 cycloalkyl groups and C5 to C6 cycloalkenyl groups provided theyare within a chemically acceptable range.

Examples of these substituents include halogen atoms such as a fluorineatom, chlorine atom, bromine atom or iodine atom; hydroxyl groups; C1 toC20 alkoxy groups such as a methoxy group, ethoxy group, n-propoxygroup, i-propoxy group, n-butoxy group, s-butoxy group, i-butoxy groupor t-butoxy group; C7 to C18 aralkyloxy groups such as a benzyloxygroup, α,α-dimethylbenzyloxy group or phenethyloxy group; acylaminogroups such as an acetylamino group or benzoylamino group; sulfonylaminogroups such as a methanesulfonylamino group or toluenesulfonylaminogroup; N-alkyl-N-acylamino groups such as an N-methyl-N-acetylaminogroup, N-ethyl-N-acetylamino group, N-methyl-N-benzoylamino group orN-ethyl-N-acylamino group; N-alkyl-N-alkylsulfonylamino groups such asN-methyl-N-methylsulfonylamino group or N-ethyl-N-methylsulfonylaminogroup; oxygen-containing heterocyclic groups such as a phthalimidogroup, furanyl group, pyranyl group or dioxolanyl group; C1 to C20 alkylgroups such as a methyl group, ethyl group, n-propyl group, i-propylgroup, n-butyl group, s-butyl group, t-butyl group, n-pentyl group orn-hexyl group; C3 to C8 cycloalkyl groups such as a cyclopropyl group,cyclobutyl group or cyclopentyl group; C2 to C20 alkenyl groups such asa vinyl group, n-propenyl group, i-propenyl group, n-butenyl group,sec-butenyl group, 1,3-butadienyl group, n-pentenyl group, 2-pentenylgroup, 3-pentenyl group or hexenyl group; C5 to C6 cycloalkenyl groupssuch as a 1-cyclopentenyl group, 2-cyclopentenyl group, 1-cyclohexenylgroup, 2-cyclohexenyl group or 3-cyclohexenyl group; C7 to C18 aralkylgroups such as a benzyl group, α,α-dimethylbenzyl group or phenethylgroup; and C6 to C18 aryl groups such as a phenyl group, 1-naphthylgroup, 2-naphthyl group or 3-anthracenyl group.

There are no particular limitations on the 3-quinuclidinone derivativerepresented by formula (I) with respect to the steric configuration ofcarbon atoms substituted by R when R is not a hydrogen atom, and may anoptically active form or racemic mixture.

The 3-quinuclidinone derivative represented by formula (I) is preferablya compound represented by formula (I-1)

(wherein, R is the same as previously defined), and more preferably acompound represented by the following formulas.

Ruthenium Compound (II)

In the present invention, the ruthenium compound represented by theformula (II) (to be referred to as the “ruthenium compound (II)”) isused as an asymmetric hydrogenation catalyst.

In the formula (II), X and Y respectively and independently represent ahydrogen atom (hydride), halogen atom (halide ion), carboxylate,hydroxyl group (hydroxide ion) or C1 to C20 alkoxy group.

Examples of the halogen atom include a fluorine atom, chlorine atom,bromine atom and iodine atom.

Examples of the carboxylate include anions of C2 to C20 carboxylic acidssuch as acetic acid, propionic acid or n-butanoic acid.

Examples of the C1 to 20 alkoxy groups include a methoxy group, ethoxygroup, n-propoxy group, i-propoxy group, n-butoxy group, s-butoxy group,i-butoxy group and t-butoxy group.

Px represents a phosphine ligand, there are no particular limitationsthereon provided it can be a ligand of the ruthenium compoundrepresented by the formula (II), and it is preferably an opticallyactive ligand.

Examples of the phosphine ligand include monodentate phosphine ligandsrepresented by the formula: PR_(A)R_(B)R_(C), and bidentate phosphineligands represented by the formula: R_(D)R_(E)P-Q-PR_(F)R_(G).

In the formulas PR_(A)R_(B)R_(C) and R_(D)R_(E)P-Q-PR_(F)R_(G), R_(A) toR_(G) respectively and independently represent an unsubstituted orsubstituted C1 to C20 alkyl group such as a methyl group, ethyl group,n-propyl group, i-propyl group, n-butyl group, s-butyl group, t-butylgroup, n-pentyl group or n-hexyl group; an unsubstituted or substitutedC6 to C14 aryl group such as a phenyl group, 1-naphthyl group or2-naphthyl group; or an unsubstituted or substituted C3 to C8 cycloalkylgroup such as a cyclopropyl group, cyclopentyl group or cyclohexylgroup.

In addition, any two of R_(A), R_(B) and R_(C) may bond to form anunsubstituted or substituted carbon ring, or R_(D) and R_(E) or R_(F)and R_(G) may bond to form an unsubstituted or substituted carbon ring.

Moreover, two of R_(A), R_(B) and R_(C) may bond to form anunsubstituted or substituted heterocyclic group, and R_(D) and R_(E)and/or R_(F) and R_(G) may bond to form an unsubstituted or substitutedC3 to C6 heterocyclic group such as a phosphotane group, phosphotanegroup, phosphinane group or phosphepane group.

Q represents an unsubstituted or substituted C1 to C5 alkylene groupsuch as a methylene group, ethylene group, trimethylene group orpropylene group; an unsubstituted or substituted C3 to C8 cycloalkylenegroup such as a xylenediyl group, cyclopropylene group, cyclobutylenegroup, cyclopentylene group, cyclohexylene group or bicycloheptenediylgroup; an unsubstituted or substituted C6 to C22 arylene group such as aphenylene group, naphthylene group, ferrocenylene group,9,10-dihydroanthracenediyl group or xanthenediyl group(xanthene-4,5-diyl group); an unsubstituted or substituted divalentgroup of an axially symmetrical compound such as a1,1′-biphenyl-2,2′-diyl group, 3,3′-bipyridyl-4,4-diyl group,4,4-bipyridyl-3,3′-diyl group, 1,1′-binaphthyl-2,2′-diyl group or1,1′-binaphthyl-7,7-diyl group; or a divalent group of ferrocene.

There are no particular limitations on the type or number of thesubstituents of each of the unsubstituted or substituted groupsindicated above provided they are within a chemically acceptable range.Specific examples of these substituents include the same substituents asthose listed as examples of substituents of the aforementioned R, suchas C7 to C18 aralkyl groups.

Specific examples of monodentate phosphine ligands represented by theformula: PR_(A)R_(B)R_(C) include tertiary phosphines in which R_(A),R_(B) and R_(C) are all the same groups such as tri ethylphosphine,triethylphosphine, tributylphosphine, triphenylphosphine,tricyclohexylphosphine or tri(p-tolyl)phosphine; tertiary phosphines inwhich two of R_(A), R_(B) and R_(C) are the same groups such asdiphenylmethylphosphine, dimethylphenylphosphine,diisopropylmethylphosphine, 1-[2-(diphenylphosphino)ferrocenyl]ethylmethyl ether or 2-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl; andtertiary phosphines in which all of R_(A), R_(B) and R_(C) are differentsuch as cyclohexyl(O-anisyl)-methylphosphine, ethylmethylbutylphosphine,ethylmethylphenylphosphine or isopropylethylmethylphosphine.

Examples of bidentate phosphine ligands represented by the formula:R_(D)R_(E)P-Q-PR_(F)R_(G) include bisdiphenylphosphinomethane,1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane,1,4-bis(diphenylphosphino)butane, 1,2-bis(dimethylphosphino)ethane,1,3-bis(dimethylphosphino)propane,9,9-dimethyl-4,5-bis[bis(2-methylphenyl)phosphino]xanthene (XANTPHOS)and 2,2T-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP).

In addition, BINAP derivatives, which have a substituent such as ahalogen atom, alkyl group, halogenated alkyl group, aryl group or alkoxygroup on the naphthyl ring and/or benzene ring of BINAP, are alsopreferable examples of bidentate phosphine ligands.

Specific examples of the aforementioned BINAP derivatives includebidentate phosphine ligands such as2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl or2,2′-bis[bis(3,5-dimethylphenyl)phosphino]-1,1′-binaphthyl;1-[2-(diphenylphosphino)ferrocenyl]ethyldi-t-butylphosphine;1-[2-(diphenylphosphino)ferrocenyl]ethyldiphenylphosphine;1-[2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine; bidentatephosphine ligands having a substituent such as a halogen atom, alkylgroup, halogenated alkyl group, aryl group or alkoxy group on a benzenering of the aforementioned ferrocene derivatives;1-butoxycarbonyl-4-dicyclohexylphosphino-2-(diphenylphosphinomethyl)pyrrolidine;1-butoxycarbonyl-4-diphenylphosphino-2-(diphenylphosphinomethyl)pyrrolidine;

2,2′-bis(dicyclohexylphosphino)-6,6′-dimethyl-1,1′-biphenyl;2,2′-bis(diphenylphosphino)-6,6′-dimethoxy-1,1′-biphenyl (MeO-BIPHEP);2,2′-bis(diphenylphosphino)-5,5′-dichloro-6,6′-dimethoxy-1,1′-biphenyl(Cl-MeO-BIPHEP); 5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole(SEGPHOS); bidentate phosphine ligands having a substituent such as ahalogen atom, alkyl group, halogenated alkyl group, aryl group or alkoxygroup on a 1,3-benzodioxole ring and/or benzene ring of SEGPHOS;2,3-bis(diphenylphosphino)butane;1-cyclohexyl-1,2-bis-(diphenylphosphino)ethane;2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis-(diphenylphosphino)butane;

1,2-bis(2,5-diethylphosphorano)benzene (Et-DUPHOS);1,2-bis(2,5-di-t-isopropylphosphorano)benzene;1,2-bis(2,5-dimethylphosphorano)benzene (Me-DUPHOS);5,6-bis(diphenylphosphino)-2-norbornene;N,N′-bis(diphenylphosphino)-N,N′-bis(1-phenylethyl)ethylenediamine;1,2-bis(diphenylphosphino)propane; 2,3-bis(diphenylphosphino)butane(CHIRAPHOS); 2,4-bis(diphenylphosphino)pentane (BDPP);4,5-bis(diphenylphosphinomethyl)-2,2′-dimethyl-1,3-dioxolane (DIOP);

C3-TUNEPHOS; PHANEPHOS; Me-BPE; SYNPHOS; SDP;1,2-bis(t-butylmethylphosphino)ethane;1,2-bis[(2-methoxyphenyl)(phenyl)phosphino]ethane (DIPAMP);2,2′,6,6′-tetramethoxy-4,4′-bis(diphenylphosphino)-3,3′-bipyridine; and,1-Boc-4-diphenylphosphino-2-(diphenylphosphinomethyl)pyrrolidine.

In addition, in bidentate phosphine ligands represented by the formula:R_(D)R_(E)P-Q-PR_(F)R_(G), Q may bond with R_(D) and R_(F) to form abisheterocycle containing a phosphorous atom. Examples of thesebisheterocycles include bisphosphotane, bisphosphorane, bisphosphinaneand bisphosphepane.

Specific examples of bidentate phosphine ligands represented by theformula: R_(D)R_(E)P-Q-PR_(F)R_(G), in which Q has bonded with R_(D) andR_(F) to form a bisheterocycle containing a phosphorous atom include1,1′-di-t-butyl-[2,2′]-diphosphoranyl (TANGPHOS),2,2′-di-t-butyl-2,3,2′,3′-tetrahydro-1H, 1′H-[1,1′]-biisophosphindolyl(DUANPHOS),4,4′-di-t-butyl-4,4′,5,5′-tetrahydro-3,3′-bi-3H-dinaphtho[2,1-c:1′,2′-e]phosphepine (BINAPINE), and 1,2-bis{4,5-dihydro-3H-dinaphtho[1,2-c:2′, 1′-e]phosphepino}benzene(BINAPHANE).

In the formula (II), n represents 1 or 2.

In the formula (II), [R¹R²C*(NR³R⁴)-A-R⁵R⁶C*(NR⁷R⁸)] represents anoptically active diamine ligand.

In formula (II), * indicates that the carbon atom is an optically activecarbon atom.

R¹ to R⁸ respectively and independently represent a hydrogen atom, anunsubstituted or substituted C1 to C20 alkyl group, an unsubstituted orsubstituted C2 to C20 alkenyl group, an unsubstituted or substituted C3to C8 cycloalkyl group, an unsubstituted or substituted C5 to C6cycloalkenyl group, an unsubstituted or substituted C7 to C18 aralkylgroup or an unsubstituted or substituted C6 to C18 aryl group.

Specific examples of unsubstituted or substituted C1 to C20 alkylgroups, unsubstituted or substituted C2 to C20 alkenyl groups,unsubstituted or substituted C3 to C8 cycloalkyl groups, unsubstitutedor substituted C5 to C6 cycloalkenyl groups, unsubstituted orsubstituted C7 to C18 aralkyl groups and unsubstituted or substituted C6to C18 aryl groups of R¹ to R⁸ include the same as those listed asexamples for the aforementioned R.

In addition, either of R¹ and R² may bond with either of R³ and R⁴, andeither of R⁵ and R⁶ may bond with either of R⁷ and R⁸, to form a ring.Examples of cyclic residues formed by either of R¹ and R² bonding witheither of R³ and R⁴ or either of R⁵ and R⁶ bonding with either of R⁷ andR⁸ include a 2-pyrrolidinyl group, 2-indolyl group, 2-piperidinyl group,1,2,3,4-tetrahydroisoquinolin-2-yl group and1,2,3,4-tetrahydroxyisoquinolin-3-yl group.

Among these examples, R¹ to R⁸ are all preferably hydrogen atoms fromthe viewpoint of ease of synthesis and availability.

In addition, in the case A described below is an unsubstituted orsubstituted C1 to C3 alkylene group, either of R¹ and R² may bond witheither of R⁵ and R⁶ to form a ring.

* indicates that the carbon atom is an optically active carbon atom.

A represents an unsubstituted or substituted C1 to C3 alkylene groupthat may have an ether bond, an unsubstituted or substituted C3 to C8cycloalkylene group, an unsubstituted or substituted C6 to C22 arylenegroup or an unsubstituted or substituted divalent heterocyclic group.

Examples of C1 to C3 alkylene groups that may have an ether bond of Ainclude a methylene group, ethylene group, propylene group, trimethylenegroup or —CH₂—O—CH₂— group.

Examples of C3 to C8 cycloalkylene groups and C6 to C22 arylene groupsof A include the same groups as those listed as examples for theaforementioned Q.

Examples of divalent heterocyclic groups of A include divalentheterocyclic groups of 5-membered rings such as furan-3,4-diyl,tetrahydrofuran-3,4-diyl, 1,3-dioxolan-4,5-diyl,2-oxo-1,3-dioxolan-4,5-diyl, thiophen-3,4-diyl, pyrrol-3,4-diyl or2-imidazolidinone-4,5-diyl; divalent heterocyclic groups of 6-memberedrings such as 1,4-dioxolan-2,3-diyl, pyrazin-2,3-diyl orpyridazin-4,5-diyl; and, divalent condensed heterocyclic groups such as1,4-benzoxolane-2,3-diyl.

There are no particular limitations on substituents in theaforementioned C1 to C3 alkylene groups that may have an ether bond, C3to C8 cycloalkylene groups, C6 to C22 arylene groups and divalentheterocyclic groups provided they are chemically acceptable. Specificexamples of these substituents include the same substituents as thoselisted as examples of substituents of C7 to C18 aralkyl groups of theaforementioned R.

Furthermore, in the case A is an ethylene group having respectivesubstituents on different carbon atoms, two substituents of the ethylenegroup may bond to form a hydrocarbon ring. Specific examples of A insuch cases include divalent hydrocarbon rings such ascyclopentan-1,2-diyl, cyclohexan-1,2-diyl and 1,2-phenylene.

The ruthenium compound (II) used in the present invention is preferablya ruthenium compound represented by the formula (II-1):Ru(X)(Y)(Px)_(n)[R¹C*H(NR³R⁴)-A-R¹C*H(NR³R⁴)]  (II-1)(wherein, X, Y, Px, n, R¹, R³, R⁴, * and A are the same as previouslydefined), more preferably a ruthenium compound represented by theformula (II-2):Ru(X)(Y)(Px)_(n)[R¹C*H(NH₂)-A-R¹C*H(NH₂)]  (II-2)(wherein, X, Y, Px, n, R¹, * and A are the same as previously defined),and particularly preferably a ruthenium compound represented by theformula (II-3):Ru(X)₂(Pxx)[R¹C*H(NH₂)-A-R¹C*H(NH₂)]  (II-3)(wherein, X, R¹, * and A are the same as previously defined, and Pxxrepresents an optically active phosphine ligand).

More preferable examples of diamine ligands represented by the formula(II-3) include optically active diaminopentane, optically activediaminohexane, optically active bis(2-aminopropyl)ether, opticallyactive bis(2-amino-2-phenylethyl)ether, optically active1,3-diamino-1,3-diphenylpropane, optically active1,4-diamino-1,4-diphenylbutane, optically active1,4-diamino-1,4-dicyclohexylbutane, optically active1,2-bis(1-aminoethyl) cyclopentane, optically active1,1-bis(1-aminoethyl)cyclopentane, optically active1,2-bis(1-aminoethyl)cyclohexane, optically active1,2-bis(1-aminoethyl)benzene,4R,5R-di(1R-aminoethyl)2,2-dimethyl-[1,3]dioxolane,4S,5S-di(1S-aminoethyl)2,2-dimethyl-[1,3]dioxolane,4R,5R-di(1S-aminoethyl)2,2-dimethyl-[1,3]dioxolane and4S,5S-di(1R-aminoethyl)2,2-dimethyl-[1,3]dioxolane.

Production of 3-Quinuclidinol Derivative

The production process of the present invention preferentially producesany optically active 3-quinuclidinol derivative (III) by an asymmetrichydrogenation reaction using the 3-quinuclidinone derivative (I) as astarting raw material and the ruthenium compound (II) as a hydrogenationcatalyst.

The asymmetric hydrogenation reaction is carried out by asymmetricallyreducing the 3-quinuclidinone derivative (I) in the presence of theruthenium compound (II) and in the presence of hydrogen gas at aprescribed pressure or a hydrogen donor by adding a base as desired.

In addition, in the present invention, after forming the rutheniumcompound (II) by adding a ruthenium complex having a phosphine ligandand a diamine compound which serve as production raw materials of theruthenium compound (II) to reaction system separately, and adding a baseas necessary, an asymmetric hydrogenation reaction can be carried outwithin the reaction system by adding a substrate to the reaction system,without removing the ruthenium compound (II).

Although varying according to the size of the reaction container andcatalyst activity, the amount of the ruthenium compound (II) used as acatalyst is normally within the range of 1/5,000 to 1/200,000 timesmoles, and preferably within the range of 1/10,000 to 1/100,000 timesmoles, the reaction substrate in the form of the 3-quinuclidinone (I).

Examples of bases used include organic bases such as triethylamine,diisopropylethylamine, pyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO)or 1,6-diazabicyclo[5.4.0]undec-7-ene (DBU); metal alkoxides such assodium methoxide, sodium ethoxide, potassium t-butoxide, magnesiummethoxide or magnesium ethoxide; organic lithium compounds such asn-butyl lithium; lithium amides such as lithium diisopropylamide (LDA)or lithium bistrimethylsilylamide; alkaline metal hydroxides such aslithium hydroxide, sodium hydroxide or potassium hydroxide; alkalineearth metal hydroxides such as magnesium hydroxide or calcium hydroxide;alkaline metal carbonates such as sodium carbonate or potassiumcarbonate; alkaline metal bicarbonates such as sodium bicarbonate orpotassium bicarbonate; alkaline earth metal carbonates such as magnesiumcarbonate or calcium carbonate; and, metal hydrides such as sodiumhydride or calcium hydride.

The amount of base added is 2 times moles or more and preferably withinthe range of 2 to 50,000 times moles the ruthenium compound (II).

The asymmetric hydrogenation reaction can be carried out in a suitablesolvent. There are no particular limitations on the solvent usedprovided it solubilizes the substrate and catalyst without impairing thereaction. Specific examples of solvents include alcohols such asmethanol, ethanol, n-propanol, i-propanol, i-butanol or benzyl alcohol;aromatic hydrocarbons such as benzene, toluene or xylene; aliphatichydrocarbons such as pentane or hexane; halogenated hydrocarbons such asdichloromethane, chloroform, trichloromethane, carbon tetrachloride or1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran (THF),1,2-dimethoxyethane or 1,4-dioxane; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide,1,3-dimethylimidazolidine, 1,3-dimethyl-2-imidazolidinone,N-methylpyrrolidone or hexamethylphosphoric triamide (HMPT); nitrilessuch as acetonitrile or benzonitrile; and, DMSO.

One type of these solvents can be used alone or two or more types can beused as a mixture. Among these, alcohols are used preferably since thereaction products are alcohol compounds.

The amount of solvent used depends on the solubility of the3-quinuclidinone derivative (I) and economic efficiency, and althoughthe reaction also proceeds in the absence of solvent or in a state nearhighly diluted conditions depending on the case, the amount of solventused is normally within the range of 10 to 10,000 parts by weight, andpreferably within the range of 50 to 1,000 parts by weight, based on 100parts by weight of the 3-quinuclidinone derivative (I).

The pressure of the hydrogen is normally 1×10⁵ to 2×10⁷ Pa, and ispreferably within the range of 3×10⁵ to 1×10⁷ Pa from the viewpoint ofpracticality.

A hydrogen storage alloy or diimide and the like can be used for thehydrogen donor used. The amount used is normally within the range of 1to 100 times equivalents the 3-quinuclidinone derivative (I).

The reaction temperature is normally within the range of −50 to +200° C.and preferably within the range of 0 to 100° C.

In addition, although varying according to the reaction substrateconcentration and reaction conditions such as temperature and pressure,the reaction temperature is normally from several minutes to severaldays.

There are no particular limitations on the type of reaction, and thereaction may be of a batch type or continuous type.

Following completion of the reaction, isolation and purification arecarried out using ordinary organic synthetic chemistry techniques toenable the obtaining of the optically active 3-quinuclidinol derivative(III).

Structures of target compounds can be identified and confirmed by knownanalytical means such as elementary analysis, NMR, IR or massspectroscopy.

An optically active 3-quinuclidinol derivative obtained in the mannerdescribed above is useful as a production raw material of activeingredients of pharmaceuticals or production intermediates of thoseactive ingredients.

3-Quinuclidinol Derivative (III)

According to the present invention, an optically active 3-quinuclidinolderivative represented by the formula (III) (to be referred to as the3-quinuclidinol derivative (III)) can be obtained.

Namely, in the case of a compound represented by the formula (I), any3-quinuclidinol derivative (III) having an optically active carbon atomindicated with an * can be obtained by asymmetric hydrogenation reactionusing the ruthenium compound (II) as a hydrogenation catalyst. This isthe result of any enantiomeric isomer being preferentially obtainedcorresponding to an enantiomer of the ruthenium compound (II) used.

In addition, in the present invention, the 3-quinuclidinol derivativerepresented by the formula (III-1) can be obtained in the case of usingthe 3-quinuclidinone derivative represented by the formula (I-1) as astarting raw material.

In the case of a compound represented by the formula (I-1), if areaction is carried out by using as a starting raw material3-quinuclidinone in which R in the formula is a hydrogen atom and usingthe ruthenium compound (II) as a catalyst, either of the3-quinuclidinols (IIIa) and (IIIb) represented by the following formulascan be obtained.

In addition, in the case of a compound represented by the formula (I-1),if an asymmetric hydrogenation reaction is carried out using a3-quinuclidinone derivative represented by formula (I-1) as a startingraw material in which R in the formula is that other than a hydrogenatom and using the ruthenium compound (II) as a hydrogenation catalyst,either of the 3-quinuclidinol derivatives (IIIc) and (IIId) representedby the following formulas can be obtained:

(wherein, R is the same as previously defined).

An optically active 3-quinuclidinol derivative obtained by theproduction process of the present invention is useful as a productionraw material of active ingredients of pharmaceuticals or productionintermediates of those active ingredients.

EXAMPLES

Although the following provides a more detailed explanation of thepresent invention through examples thereof, the present invention is notlimited to only these examples.

Furthermore, the apparatuses used to measure physical properties in eachof the examples are as indicated below.

-   (1) Varian GEMINI-300 (300 MHz, Varian Inc.), JNM-A300 (300 MHz) and    JNM-A400 (400 MHz, JEOL Ltd.)-   (2) Measurement of optical rotation: Polarimeter, JASCO DIP-360    (Jasco Corp.)-   (3) High-performance liquid chromatograph: LC-10Advp, SPD-10Avp    (Shimadzu Corp.)-   (4) Gas chromatograph: GC-17A, CR-7A Plus (Shimadzu Corp.) and    GC-353B (GL Sciences Inc.)

The ruthenium compound (II) used was synthesized in accordance with theprocess described in Japanese Unexamined Patent Application, FirstPublication No. 2002-284790.

Example 1

1.63 g (13 mmol) of the 3-quinuclidinone (I) were added to a 50 mlSchlenk tube and after reducing pressure inside the vessel with a vacuumpump, argon was sealed inside. This procedure was repeated three timesto replace the inside of the vessel with argon 12.7 ml of 2-propanol and0.26 ml (0.26 mmol) of a 2-propanol solution of potassium tert-butoxide(1.0M) were respectively added to the vessel with a glass syringe. Aftercompletely dissolving the 3-quinuclidinone using an ultrasonic device,the solution was frozen at the temperature of liquid nitrogen. Afterreducing the pressure inside the vessel with a vacuum pump, the solutionwas thawed using a heat gun. This freezing-degassing procedure wasrepeated three times to obtain a substrate solution.

A polytetrafluoroethylene-coated stirrer bar and 1.4 mg of the rutheniumcompound (II) in the form of(S)-1,1′-binapthyl-2,2′-bis(di-p-tolyl)phosphine ruthenium (II)dichloride (2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine complex(1.3 μmol, S/C=(substrate: 13 mmol)/(ruthenium compound (II):1.3μmol)=10,000) were added to a 100 ml stainless steel autoclave (providedwith a glass inner tube) followed by replacing the inside of the vesselwith argon. Next, the substrate solution was transferred to theautoclave using a polytetrafluoroethylene tube.

The autoclave was connected to a hydrogen tank using a hydrogen feedtube and hydrogen at 0.2 MPa was released 10 times to replace air insidethe feed tube with hydrogen. Subsequently, hydrogen at 1.0 MPa wassealed in the autoclave vessel followed immediately by releasinghydrogen until the pressure reached 0.2 MPa, and this procedure wasrepeated 10 times to replace the inside of the vessel with hydrogen.Finally, hydrogen was filled to a pressure of 2.0 MPa followed bystirring for 5 hours at 20 to 25° C.

Following completion of the reaction, 146.1 ml (1.105 mmol) ofdistillation purified tetralin were added to the reaction solution as aninternal standard followed by stirring to achieve uniformity. When thereaction mixture was analyzed by gas chromatography, 13 mmol of(R)-3-quinuclidinol (3-R) were determined to have been formed at aenantiomeric excess of 97% ee(R) (yield: 100%).

Example 2

The same reaction as Example 1 was carried out with the exception ofusing (S)-1,1′-binaphthyl-2,2′-bis(diphenyl) phosphine ruthenium (II)dichloride (2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine complexfor the ruthenium compound (II) to obtain (R)-3-quinuclidinol (3-R).S/C, conversion rate and enantiomeric excess are indicated below.

S/C: 10,000

Conversion rate: 100%

Enantiomeric excess: 97% ee(R)

Example 3

The same reaction as Example 1 was carried out with the exception ofusing (S)-1,1′-binaphthyl-2,2′-bis(diphenyl) phosphine ruthenium (II)dichloride (R,R)-hexane-2,5-diamine complex for the ruthenium compound(II) to obtain (R)-3-quinuclidinol (3-R). S/C, conversion rate andenantiomeric excess are indicated below.

S/C: 20,000

Conversion rate: 100%

Enantiomeric excess: 95% ee(R)

Example 4

1.63 g (13 mmol) of the 3-quinuclidinone (I), 1.1 mg (1.3 μmol) of{[(S)-(6,6′-dimethyl-1,1′-biphenyl-2,2′-diyl)-bis(diphenylphosphine)]ruthenium(II) dichloride (DMF)n} complex, 12.7 ml of 2-propanol and 31 μl (1.55μmol) of a 0.05 M 2-propanol solution of(2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine were added to anautoclave in which the inside had been replaced with argon followed bycarrying out a degassing procedure and stirring for 30 minutes at roomtemperature. 0.26 mL (0.26 mmol) of a 2-propanol solution of potassiumtert-butoxide (1.0 M) were added thereto followed by stirring for 16hours at 20 to 25° C. at a hydrogen pressure of 2.0 MPa to obtain(R)-3-quinuclidinol (3-R). S/C, conversion rate and enantiomeric excessare indicated below.

S/C: 10,000

Conversion rate: 100%

Enantiomeric excess: 95% ee(R)

Example 5

1.63 g (13 mmol) of the 3-quinuclidinone (I), 1.1 mg (1.3 μmol) of{[(S)-(6,6′-dimethyl-1,1′-biphenyl-2,2′-diyl)-bis(di-p-tolylphosphine)]ruthenium(II) dichloride (DMF)n} complex, 12.7 ml of 2-propanol and 31 μl (1.55μmol) of a 0.05 M 2-propanol solution of(2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine were added to anautoclave in which the inside had been replaced with argon followed bycarrying out a degassing procedure and stirring for 30 minutes at roomtemperature. 0.26 mL (0.26 mmol) of a 2-propanol solution of potassiumtert-butoxide (1.0 M) were added thereto followed by stirring for 16hours at 20 to 25° C. at a hydrogen pressure of 2.0 MPa to obtain(R)-3-quinuclidinol (3-R). S/C, conversion rate and enantiomeric excessare indicated below.

S/C: 10,000

Conversion rate: 100%

Enantiomeric excess: 96% ee(R)

Example 6

The same reaction as Example 1 was carried out with the exception ofusing (R)-1,1′-binaphthyl-2,2′-bis(diphenyl) phosphine ruthenium (II)dichloride(1S,2S,3S,4S)-2,3-O-isopropylidene-1,4-diphenylbutane-1,4-diaminecomplex for the ruthenium compound (II) to obtain (S)-3-quinuclidinol(3-S). S/C, conversion rate and enantiomeric excess are indicated below.

S/C: 5,000

Conversion rate: 100%

Enantiomeric excess: 95% ee(S)

Example 7

The same reaction as Example 1 was carried out with the exception ofusing (R)-1,1′-binaphthyl-2,2′-bis(di-p-tolyl) phosphine ruthenium (II)dichloride (S,S)-hexane-2,5-diamine complex for the ruthenium compound(II) to obtain (S)-3-quinuclidinol (3-S). S/C, conversion rate andenantiomeric excess are indicated below.

S/C: 10,000

Conversion rate: 100%

Enantiomeric excess: 97% ee(S)

Example 8

The same reaction as Example 1 was carried out with the exception ofusing (R)-1,1′-binaphthyl-2,2′-bis(di-p-tolyl) phosphine ruthenium (II)dichloride (S,S)-1,4-diphenylbutane-1,4-diamine complex for theruthenium compound (II) to obtain (S)-3-quinuclidinol (3-S). S/C,conversion rate and enantiomeric excess are indicated below.

S/C: 10,000

Conversion rate: 100%

Enantiomeric excess: 98% ee(S)

Example 9

397.7 mg (1.30 mmol) of a racemic mixture of2-benzhydrylquinuclidin-3-one (1-2) and 1.2 mg (1.3 μmol) of(S)-1,1′-binaphthyl-2,2′-bis(diphenyl)phosphine ruthenium (II)dichloride (R,R)-hexane-2,5-diamine complex were placed in an autoclavein which the inside had been replaced with argon. After adding 6.4 ml of2-propanol thereto and degassing, 0.13 mL (0.13 mmol) of a 2-propanolsolution of potassium tert-butoxide (1.0 M) were added thereto followedby stirring for 18 hours at 20 to 25° C. at a hydrogen pressure of 1.0MPa. After concentrating the reaction solution, analysis of the crudepurification product by 1H-NMR indicated that only the syn form had beenformed. The reaction solution was then purified by silica gel columnchromatography (developing solvent: n-hexane:ethyl acetate=3:1 (volumeratio)) to obtain 382 mg (1.30 mmol, yield: 96%) of(2S,3S)-2-benzhydrylquinuclidin-3-ol (3-2). The optical purity of thissubstance as measured by high-performance liquid chromatography (eluent:acetonitrile:0.02 M aqueous disodium hydrogen phosphate=6:4 (volumeratio), column: CHIRALCEL OD-RH, Daicel Chemical Industries, Ltd.) was96% ee.

Example 10

The same reaction as Example 9 was carried out with the exception ofusing (S)-1,1′-binaphthyl-2,2″-bis(diphenyl) phosphine ruthenium (II)dichloride (2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine complexfor the ruthenium compound (II) to obtain(2S,3S)-2-benzhydrylquinuclidin-3-ol (3-2) at a yield of 99% and opticalpurity of >99% ee.

Example 11

The same reaction as Example 9 was carried out with the exception ofusing the compound represented by the following formula (12) for theruthenium compound (II) to obtain (2S,3S)-2-benzhydrylquinuclidin-3-ol(3-2) at a yield of 96% and optical purity of >99.6% ee.

Example 12

398.0 mg (1.30 mmol) of a racemic mixture of2-benzhydrylquinuclidin-3-one (1-2), 1.1 mg (1.3 μmol) of{[(S)-(6,6T-dimethyl-1,1′-biphenyl-2,2′-diyl)-bis(diphenylphosphine)]ruthenium(II) dichloride (DMF)n} complex, 6.4 ml of 2-propanol and 31 μl (1.55μmol) of a 0.05 M 2-propanol solution of(2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine were added to anautoclave in which the inside had been replaced with argon followed bydegassing and stirring for 30 minutes at room temperature. 0.13 mL (0.13mmol) of a 2-propanol solution of potassium tert-butoxide (1.0 M) wereadded thereto followed by stirring for 18 hours at 20 to 25° C. at ahydrogen pressure of 1 MPa. The same post-treatment procedure as Example7 was carried out to obtain (2S,3S)-2-benzhydrylquinuclidin-3-ol (3-2)at a yield of 97% and optical purity of >99% ee.

Industrial Applicability

According to the present invention, an optically active 3-quinuclidinolderivative of high optical purity can be produced at high attainmentrates for enantiomeric excess or diastereomeric excess and catalystefficiency by using a readily available ruthenium compound as anasymmetric reduction catalyst, thereby making the present inventionextremely industrially useful.

The invention claimed is:
 1. A process for producing an optically active3-quinuclidinol derivative represented by formula (III-1):

wherein, R represents a hydrogen atom, an unsubstituted or substitutedC1 to C20 alkyl group, an unsubstituted or substituted C2 to C20 alkenylgroup, an unsubstituted or substituted C3 to C8 cycloalkyl group, anunsubstituted or substituted C5 to C6 cycloalkenyl group, anunsubstituted or substituted C7 to C18 aralkyl group or an unsubstitutedor substituted C6 to C18 aryl group, and * represents an opticallyactive carbon atom, and ** represents an optically active carbon atom inthe case R is other than a hydrogen atom, comprising: asymmetricallyhydrogenating a 3-quinuclidinone derivative represented by formula(I-1):

wherein, R is the same as previously defined in the presence of aruthenium compound represented by the formula (II-2):Ru(X)(Y)(Px)_(n)[R¹H(NH₂)C*-A-C*R¹H(NH₂)]  (II-2) wherein, X and Yrepresent a hydrogen atom, or a chlorine atom; Px represents a phosphineligand selected from a group consisting of(6,6′-dimethyl-1,1′-biphenyl-2,2′diyl)-bis(diphenylphosphine) and(6,6′-dimethyl-1,1′-biphenyl-2,2′diyl)-bis(di-p-tolylphosphine); nrepresents 1; R¹ represents an unsubstituted or substituted C1 alkylgroup or an unsubstituted or substituted C6 aryl group; * is the same aspreviously defined; and, A represents an unsubstituted or substituted C1to C3 alkylene group that may have ether bond(s), an unsubstituted orsubstituted C3 to C8 cycloalkylene group or an unsubstituted orsubstituted divalent heterocyclic group.
 2. A process for producing anoptically active 3-quinuclidinol derivative represented by formula(III-1):

wherein, R represents a hydrogen atom, an unsubstituted or substitutedC1 to C20 alkyl group, an unsubstituted or substituted C2 to C20 alkenylgroup, an unsubstituted or substituted C3 to C8 cycloalkyl group, anunsubstituted or substituted C5 to C6 cycloalkenyl group, anunsubstituted or substituted C7-C18 aralkyl group or an unsubstituted orsubstituted C6 to C18 aryl group, and * represents an optically activecarbon atom, and ** represents an optically active carbon atom in thecase R is other than a hydrogen atom, comprising: asymmetricallyhydrogenating a 3-quinuclidinone derivative represented by formula(I-1):

wherein, R is the same as previously defined in the presence of aruthenium compound represented by the formula (II-3):R(X)₂(Pxx)[R¹H(NH₂)C*-A-C*R¹H(NH₂)]  (II-3) wherein X represents ahydrogen atom, or a chlorine atom; Pxx represents a phosphine ligandselected from a group consisting of(6,6′-dimethyl-1,1′-biphenyl-2,2′diyl)-bis(diphenylphosphine) and(6,6′-dimethyl-1,1′-biphenyl-2,2′diyl)-bis(di-p-tolylphosphine); R¹represents an unsubstituted or substituted C1 alkyl group or anunsubstituted or substituted C6 aryl group; * is the same as previouslydefined; and A represents an unsubstituted or substituted C1 to C3alkylene group that may have ether bond(s), an unsubstituted orsubstituted C3 to C8 cycloalkylene group or an unsubstituted orsubstituted divalent heterocyclic group.